Heart Failure, Hyperkalemia
Conditions
Keywords
HF, Heart failure, hyperkalemia, chronic kidney disease, prevention of hyperkalemia in heart failure participants
Brief summary
The purpose of this study was to assess the effects of patiromer on serum potassium participants with heart failure. This study also assessed the safety and tolerability of patiromer in participants with heart failure.
Detailed description
This was a double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study in congestive heart failure participants. Depending on the outcome from the initial cohort of 100 participants (Part 1), a second cohort of 170 participants could have been enrolled (Part 2). Based on the results of Part 1 of the study, Part 2 was not conducted. Participants were randomly assigned to and received patiromer (30 g/day) or placebo for up to 28 days. All participants also received spironolactone; the initial spironolactone dose was 25 mg daily and was increased to 50 mg daily for participants who had a serum potassium ≤ 5.1 mEq/L on treatment Day 14. Study visits occurred on treatment Days 3, 7, 14, 17, 21 and 28. A safety follow-up contact was made 7 days after administration of last dose of study drug.
Interventions
DRUGpatiromer
Active investigational drug
DRUGplacebo
placebo
Sponsors
Medpace, Inc.
Relypsa, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with chronic heart failure clinically indicated to receive spironolactone therapy, aged 18 years or older with serum potassium level of 4.3 - 5.1 mEq/L at screening and baseline, AND (1) chronic kidney disease (GFR \< 60 mL/min) OR (2) documented history of hyperkalemia within the last 6 months * Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before study drug administration, during the study, and for one month after study completion * Male participants and/or their female partners of child-bearing potential must use a highly effective form of contraception during the study and for 3 months after study completion * Must sign informed consent document
Exclusion criteria
* History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery * Uncorrected hemodynamically significant primary valvular disease, known obstructive or restrictive cardiomyopathy, uncontrolled or hemodynamically unstable arrhythmia * Coronary-artery bypass graft, percutaneous intervention (e.g. cardiac, cerebrovascular, aortic), or major surgery including thoracic and cardiac, within 3 months prior to baseline or anticipated need during study participation * Heart transplant recipient, or anticipated need for transplant during study participation * Any of the following events having occurred within 3 months prior to baseline: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, transient ischemic attack or stroke * Current dialysis participant, or anticipated need for dialysis during study participation * Prior kidney transplant, or anticipated need for transplant during study participation * Metastatic, late-stage or end-stage cancer with \< 12 months life expectancy * History of alcoholism or drug/chemical abuse within 1 year * QTcB interval \> 500 msec (Bazett's correction formula) * Sustained systolic blood pressure \> 170 or \< 90 mmHg * Liver enzymes (ALT, AST) \> 3 times upper limit of normal * Use of oral cardiac medications (including loop and thiazide diuretics) that have not been stable for at least 21 days prior to baseline and are not anticipated to remain stable during study participation * Use of any IV cardiac medications within 21 days prior to baseline, or their anticipated need during study participation. * Current use of polymer-based drugs (e.g. Renagel, Kayexalate, Welchol, Colestid), other phosphate binders or potassium binders, calcium supplements, antacids (eg TUMS, Maalox), or their anticipated need during study participation * Use of aldosterone antagonist in the last 30 days prior to baseline, unless was discontinued due to hyperkalemia * Use of potassium sparing medication and/or potassium supplements in the last 30 days prior to baseline * Use of any investigational medication, 30 days or 5 half-lives whichever is longer, prior to baseline * Participants who have taken investigational product in this study, or a previous patiromer study * Inability to consume the study medication, or, in the opinion of the Investigator, inability to comply with the protocol * In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, serious intercurrent illness, or extenuating circumstance occurring or persisting, within 30 days prior to baseline, that would significantly decrease study compliance or jeopardize the safety of the participant or affect the validity of the trial results
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Serum Potassium to the End of the 28-day Treatment Period. | Baseline and Day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With a Serum Potassium Level During the 28-day Treatment Period That Was > 5.5 mEq/L. | 28 Days | Analysis based on central laboratory data. |
| Proportion of Participants Discontinuing the Study Due to Serum Potassium Elevation (Serum K+ > 5.5 mEq/L). | 28 Days | Analysis based on local laboratory data. |
| Proportion of Participants Whose Spironolactone Dose Was Increased. | 28 Days | — |
| Proportion of Participants With an Increase in Serum Potassium Level From Baseline to the End of the 28-day Treatment Period That Was ≥ 0.5 mEq/L | Baseline and Day 28 | — |
| Time to First Elevated Serum K+ > 5.5 mEq/L. | 28 Days | — |
Countries
Czechia, Georgia, Germany, Poland, Russia, Ukraine, United States
Participant flow
Recruitment details
120 subjects were randomized in Part 1 of the study (60 to each treatment group). Of these, 120 randomized subjects, 105 received either RLY5016 Powder for Suspension (n = 56) or placebo (n = 49).
Pre-assignment details
Eligible participants ≥ 18 y/o, had history of chronic HF, clinically initiated spironolactone therapy, serum K+ = 4.3 - 5.1 mEq/L at screening and baseline, and either had 1) CKD, w/ eGFR \< 60 mL/min and receiving HF therapies or 2) documented history of hyperkalemia led to discontinuation w/ aldosterone antagonist w/in 6 months prior to baseline.
Participants by arm
| Arm | Count |
|---|---|
| Patiromer Spironolactone + Patiromer
Participants received patiromer (15 g twice daily \[BID\]).
Participants also started spironolactone at a dose of 25 mg/day, which was increased to 50 mg/day after 2 weeks if the participant's serum potassium (based on local laboratory determination) was \> 3.5 mEq/L and ≤ 5.1 mEq/L. The spironolactone dose remained at 25 mg/day if the serum potassium was \> 5.1 mEq/L and ≤ 5.5 mEq/L. If, at any time, a participant's serum potassium level was confirmed to be ≤ 3.5 mEq/L or \> 5.5 mEq/L based on local laboratory data, the participant was to be discontinued from the study. | 55 |
| Placebo Spironolactone + Placebo
Participants received placebo (twice daily \[BID\]).
Participants also started spironolactone at a dose of 25 mg/day, which was increased to 50 mg/day after 2 weeks if the participant's serum potassium (based on local laboratory determination) was \> 3.5 mEq/L and ≤ 5.1 mEq/L. The spironolactone dose remained at 25 mg/day if the serum potassium was \> 5.1 mEq/L and ≤ 5.5 mEq/L. If, at any time, a participant's serum potassium level was confirmed to be ≤ 3.5 mEq/L or \> 5.5 mEq/L based on local laboratory data, the participant was to be discontinued from the study. | 49 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Prot-Specified W/D Criteria (Serum K+) | 2 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Patiromer | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 39 Participants | 35 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 14 Participants | 30 Participants |
| Age, Continuous | 68.3 years STANDARD_DEVIATION 8.66 | 68.2 years STANDARD_DEVIATION 10.46 | 68.3 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 26 Participants | 15 Participants | 41 Participants |
| Sex: Female, Male Male | 29 Participants | 34 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 56 | 1 / 49 |
| serious Total, serious adverse events | 2 / 56 | 2 / 49 |
Outcome results
Primary
Change From Baseline in Serum Potassium to the End of the 28-day Treatment Period.
Time frame: Baseline and Day 28
Population: Analysis was determined using Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Change From Baseline in Serum Potassium to the End of the 28-day Treatment Period. | -0.21 mEq/L | Standard Error 0.066 |
| Placebo | Change From Baseline in Serum Potassium to the End of the 28-day Treatment Period. | 0.23 mEq/L | Standard Error 0.072 |
p-value: <0.001ANCOVA
Secondary
Proportion of Participants Discontinuing the Study Due to Serum Potassium Elevation (Serum K+ > 5.5 mEq/L).
Analysis based on local laboratory data.
Time frame: 28 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Proportion of Participants Discontinuing the Study Due to Serum Potassium Elevation (Serum K+ > 5.5 mEq/L). | 0 percentage of participants |
| Placebo | Proportion of Participants Discontinuing the Study Due to Serum Potassium Elevation (Serum K+ > 5.5 mEq/L). | 6.1 percentage of participants |
p-value: =0.101Fisher Exact
Secondary
Proportion of Participants Whose Spironolactone Dose Was Increased.
Time frame: 28 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Proportion of Participants Whose Spironolactone Dose Was Increased. | 90.9 percentage of participants |
| Placebo | Proportion of Participants Whose Spironolactone Dose Was Increased. | 73.5 percentage of participants |
p-value: 0.022Fisher Exact
Secondary
Proportion of Participants With an Increase in Serum Potassium Level From Baseline to the End of the 28-day Treatment Period That Was ≥ 0.5 mEq/L
Time frame: Baseline and Day 28
Population: Analysis was determined using LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Proportion of Participants With an Increase in Serum Potassium Level From Baseline to the End of the 28-day Treatment Period That Was ≥ 0.5 mEq/L | 12.7 percentage of participants |
| Placebo | Proportion of Participants With an Increase in Serum Potassium Level From Baseline to the End of the 28-day Treatment Period That Was ≥ 0.5 mEq/L | 24.5 percentage of participants |
p-value: =0.136Fisher Exact
Secondary
Proportion of Participants With a Serum Potassium Level During the 28-day Treatment Period That Was > 5.5 mEq/L.
Analysis based on central laboratory data.
Time frame: 28 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Proportion of Participants With a Serum Potassium Level During the 28-day Treatment Period That Was > 5.5 mEq/L. | 7.3 percentage of participants |
| Placebo | Proportion of Participants With a Serum Potassium Level During the 28-day Treatment Period That Was > 5.5 mEq/L. | 24.5 percentage of participants |
p-value: =0.027Fisher Exact
Secondary
Time to First Elevated Serum K+ > 5.5 mEq/L.
Time frame: 28 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patiromer | Time to First Elevated Serum K+ > 5.5 mEq/L. | NA days |
| Placebo | Time to First Elevated Serum K+ > 5.5 mEq/L. | NA days |
p-value: =0.015Fisher Exact